Cross-linked polyallylamine polymers have found many therapeutic applications such as in reducing blood cholesterol levels by reducing reabsorbtion of bile acids (U.S. Pat. Nos. 5,168,530, 5,679,717, 5,693,675 and 5,607,669), decreasing the absorption of dietary iron from the gastrointestinal track (U.S. Pat. No. 5,702,696) and removing phosphate from the gastrointestinal track (U.S. Pat. No. 5,496,545). Further JP 05244915 discloses the use of cross-linked polyamine polymers as food preservatives. U.S. Pat. No. 6,290,947 describes the use of cationic polymers as toxin binding agents. The binding of one or more sugars by cross-linked hydrogel polymers are indicated in WO2001025291.
Cross-linked polyallylamine polymers having therapeutic applications include Sevelamer hydrochloride, Sevelamer carbonate and Colesevelam hydrochloride. Sevelamer Hydrochloride and Sevelamer carbonate are indicated for the control of serum phosphorus in patients with Chronic Kidney Disease (CKD) on hemodialysis. They are available in tablet form for oral use. These polymers are used to treat high blood levels of phosphorous in patients [hyperphosphatemia]. It binds phosphorous and prevents it from being absorbed into the blood stream. By binding phosphate in the gastrointestinal tract, Sevelamer hydrochloride and Sevelamer carbonate lowers the phosphate concentration in the serum. Colesevelam hydrochloride is a non-absorbed lipid lowering polymer that binds bile acids in the intestine, impeding their reabsorbtion. Colesevelam Hydrochloride is a novel polymeric hydrogel designed to treat cholesterol by binding the bile acids in the gastrointestinal tract. The bile acid bound gel is subsequently excreted in faeces. The cholesterol lowering action is derived from the body's use of cholesterol in the biosynthesis of bile acids to replace those that are excreted.
Methods to produce polyallylamine polymers and further cross-linking to produce cross-linked polymers are known. U.S. Pat. No. 4,528,347 discloses a process for producing a polymer of monoallylamine or a salt thereof by polymerizing an inorganic monoallylamine acid salt in a polar solvent in the presence of an azo type initiator. U.S. Pat. No. 4,626,577 discloses a process for making the methanolic solution of polyallylamine by treating powdered polyallylamine hydrochloride with methanolic solution of caustic alkali/ammonia by complete neutralisation. These methods however do not describe the preparation of cross-linked polymers such as Sevelamer Hydrochloride, Sevelamer carbonate and Colesevelam hydrochloride.
U.S. Pat. No. 4,605,701 discloses a process for preparing cross-linked polymer wherein cross-linking is performed with partially neutralised aqueous solution of polyallylamine using liquid medium that is immiscible with aqueous solvents. One of the difficulties in this process is that this process employs aliphatic or aromatic hydrocarbons for use as the liquid medium. Such hydrocarbons may be hazardous and expensive to dispose off. Another difficulty is that the polymerization process results in a high volume of effluents making the process difficult in terms of operation and batch cycle time. Since the polymerization occurs in heterogeneous immiscible phases, achieving consistency in the cross-linked product would depend upon number of process parameters such as mixing. It is highly important to have consistency in product quality to meet the requirements of drug product. Hence there is need to improve the process which would give product of consistent quality.
U.S. Pat. No. 6,083,495 covers an aqueous process to make Sevelamer hydrochloride from the polyallylamine hydrochloride polymer. It uses an aqueous alkaline solution for making the cross-linked polyallylamine, wherein the polyallylamine is reacted with a difunctional cross-linking agent in an aqueous alkaline solution to get the cross-linked polymer gel. Cross-linking in aqueous medium is associated with issues such as solubility of cross-linking agent as well as stoichiometric adjustment to achieve desired level of cross-linking.
U.S. Pat. No. 6,180,754 covers a process to make Sevelamer hydrochloride using a special type of reactor known as LIST reactor. It discloses a process for producing a cross-linked polyallylamine polymer by reacting a reduced salt, aqueous solution of a polyallylamine polymer with a multifunctional cross-linking agent in a special LIST reactor to give a cross-linked polyallylamine polymer. It also covers a process for producing a cross-linked polyallylamine polymer by (a) partially neutralizing an aqueous solution of polyallylamine hydrochloride polymer with aqueous sodium hydroxide, (b) ultrafiltering the partially neutralized, aqueous solution of polyallylamine polymer to give a reduced salt, aqueous solution of polyallylamine polymer, (c) concentrating the reduced salt, aqueous solution of polyallylamine polymer, (d) reacting the reduced salt, aqueous solution of polyallylamine polymer with epichlorohydrin in a LIST reactor to give a cross-linked polyallylamine polymer, (e) drying the cross-linked polyallylamine polymer in a LIST reactor, (f) grinding and sieving the cross-linked polyallylamine polymer, and (g) isolating the cross-linked polyallylamine polymer.
U.S. Pat. No. 6,362,266 discloses a method for producing a cross-linked polyallylamine polymer by (a) reacting an aqueous solution of a polyallylamine polymer with a multifunctional cross-linking agent to give a cross-linked polyallylamine polymer; (b) washing this aqueous solution of cross-linked polyallylamine polymer with an alcohol/water solution; (c) adding a surfactant to the washed cross-linked polyallylamine polymer; (d) drying the cross-linked polyallylamine polymer; (e) grinding and sieving the cross-linked polyallylamine polymer; and (f) isolating the cross-linked polyallylamine polymer.
U.S. Pat. No. 6,525,113 discloses a process for manufacturing cross-linked polymer involving mixing (a) polyallylamine hydrochloride (b) water (c) a hydroxide/alkoxide (d) a water-miscible organic solvent/co-solvent and (e) adding a cross-linking agent to form a cross-linked polyallylamine.
U.S. Pat. No. 6,600,011 relates to methods for purifying and drying an organic polymer hydrogel by washing the polymer hydrogel with a water wash medium and then spray drying the resulting slurry.
These aforementioned methods to produce cross-linked polymers have several disadvantages such as achieving desired industrial scale and consistency in product quality. The cross-linked product obtained from known methods requires intensive purification to produce desired quality of product on industrial scale. Hence, there is a need to provide an improved process for the preparation of cross-linked amine polymers which can overcome the above mentioned drawbacks.